UAB research scientists, along with colleagues from the University of California San Francisco and Gladstone Institutes, have discovered a direct correlation between retinal cell loss and symptoms of dementia in people with a genetic risk for frontotemporal dementia (FTD). Their findings were published recently in the September 2014 Journal of Experimental Medicine.
FTD is the second most common form of dementia, behind Alzheimer’s disease, and generally affects people under 60 years of age. Symptoms of the disorder include changes in behavior, personality, and social skills. Sufferers may also display disinhibited and obsessive-compulsive behavior.
In the inherited form of FTD which was explored in this study, a deficiency of the protein progranulin was tied to the mislocalization of another crucial protein, TDP-43, from the nucleus of the cell out to the cytoplasm, according to Erik Roberson, MD, PhD, associate professor of Neurology at UAB and co-author of the study.
“About 25 percent of the people who develop FTD have an inherited gene from a parent. Mutation of the progranulin gene disrupts the function of the protein and that reduces the amount of progranulin. That’s what causes the disease,” he says.
In studying individuals who have the mutation, the scientists discovered that the people showed significant thinning of the retina even before cognitive signs of the dementia were present. “We were studying mice as a model to understand how losing progranulin causes improper function of the brain,” Roberson says. “We checked their retinas and realized they were not working well.”
Roberson says that the relationship between neurodegeneration, progranulin and TDP-43 was previously unclear. Using the UAB mouse model of FTD, the scientists were able to investigate this connection for the first time in neurons from the retina. They identified a depletion of TDP-43 from the cell nuclei before any signs of neurodegeneration occurred, signifying that this loss may be a direct cause of the cell death associated with FTD.
To further investigate the retinal dysfunction, Timothy Kraft, PhD, associate professor in the UAB Department of Vision Sciences, collaborated with Roberson and the California scientists, who were doing similar studies on humans. Using an electroretinogram (ERG), he measured the activity of retinal ganglion cells. “The retinal changes in the mice we studied correlated very closely with anatomical loss identified in humans in the California studies,” Kraft says. “The eye is part of the brain and if there are general classes of brain disorders that might be reflected in the physiology or anatomy of the eye, this is an interesting opportunity to start making those correlations.”
Roberson says this is a significant discovery, but the scientists are working to determine what exactly it will mean to the prevention and treatment of FTD. “These are initial observations, and we need to figure out if these changes are specific to FTD or if we see the same kind of changes in the eyes of patients with other forms of dementia,” he says. “The findings could be used for diagnosis or clinical trials that ultimately could lead to a drug that would raise progranulin, for example. We also are working to unravel the mechanism by which low progranulin causes dysfunction by showing that it disrupts the transport of things in and out of the nucleus of the cell. That can be important.”
While these findings are important, Roberson says they aren’t ready for to start screening people for the disorder with an eye test. Right now, he and Kraft are focusing on raising awareness of FTD among physicians so they can recognize the symptoms and get help for patients suffering from the dementia. “This is a fairly common disease, and we are likely to have some therapies for it over the next several years,” Roberson says, “so we need to increase awareness among referring physicians. I hope these findings will do that.”